Project Summary/Abstract Dr. El-Rifai has a long standing track record in the molecular studies of cancer. He has established strong national and international collaborations for the studies of gastric and esophageal cancer. His laboratory provides unique training experiences in diverse areas of cancer research that include molecular mechanisms of tumorigenesis and drug resistance. Dr. El-Rifai's laboratory works closely with basic science (Cell biology, Cancer Biology, Statistics, Bioinformatics) and clinical Departments (Pathology, Oncology, Radiation Oncology, Surgery, Gastroenterology) for one common goal; a better clinical outcome. The laboratory has a long-standing interest in functional genomics and IntegrOmics (integrated omics) in upper GI cancers using animal models, human samples, and in vitro studies. Dr. El-Rifai leads a competitively NCI-funded research program in upper GI cancers. Dr. El-Rifai has made significant contributions in the area of gastric cancer, Barrett's esophagus and esophageal adenocarcinoma. His major research interests are in genetics, epigenetics, and cancer biology, focusing on gastrointestinal tumorigenesis and the development of novel strategies for cancer therapeutics. Dr. El-Rifai's research encompasses animal models as tools for identification of tumor development and progression. Dr. El- Rifai discovery and translational research utilize next generation sequencing, DNA and histone methylation, and miRNAs studies. He has been successful in identifying the signaling links between inflammation and cancer in gastric and esophageal adenocarcinomas, discovering novel genes that mediate drug resistance, and developing targeted therapy approaches for upper GI cancers. His work using the trefoil factor 1 knockout mouse model in conjunction with in vitro assays and human tissues samples has shown that TFF1 has potent anti-inflammatory and tumor suppressor functions, which protect against H. pylori-mediated development of gastric cancer in mouse and human. Dr. El-Rifai lab has made significant contributions to our understanding of the molecular mechanisms underlying the development and progression in Barrett's carcinogenesis. Barrett's esophagus, the main risk factor for esophageal adenocarcinoma, develops as a consequence of chronic gastroesophageal reflux disease where the distal esophagus becomes abnormally exposed to acid and bile refluxate from the stomach. The pioneering work from his lab has shown that DNA methylation wipes out the expression of several protective antioxidant enzymes, important for protecting against reflux-induced oxidative stress and DNA damage, thereby facilitating progression of metaplastic Barrett's esophagus to esophageal cancer. His studies aim to understand the molecular basis of tumorigenesis to identify and characterize targets that regulate signaling network hubs and important biological features of carcinogenesis. His laboratory pre-clinical work has been instrumental in moving some targets such as Aurora kinase A to phase I/II clinical trials in melanoma and upper GI cancers. As the director of Surgical Oncology Research, Dr. El-Rifai oversees the research development, mentors junior faculty, and participates in research training of residents and fellows in Vanderbilt, VA, and Meharry Medical College. Dr. El-Rifai has trained more than 50 personnel that included undergraduate and graduate students, postdocs, and residents. He has mentored more than 15 junior faculty members, many of whom have progressed to independent faculty positions. Cancer is a disease with no boundaries; therefore, Global Health initiatives that rely on multi-disciplinary approaches are crucial for defeating cancer. As such, Dr. El-Rifai's laboratory collaborates with several academic institutions and cancer centers worldwide that span Europe, Africa, Asia, and Latin America. Dr. El-Rifai has a firm belief that clinical and translational research founded on strong basic science discoveries is the way to win our battle against cancer.